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Trial registered on ANZCTR


Registration number
ACTRN12621000056897
Ethics application status
Approved
Date submitted
11/11/2020
Date registered
22/01/2021
Date last updated
22/01/2021
Date data sharing statement initially provided
22/01/2021
Date results information initially provided
22/01/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
A prospective trial investigating the safety and efficacy of dose-escalated radiotherapy for men with prostate cancer following insertion of a gel spacer between the prostate and rectum
Scientific title
A prospective phase II trial investigating the safety and efficacy of SpaceOAR® hydrogel in patients with prostate cancer receiving dose escalated radiotherapy to 82Gy
Secondary ID [1] 302741 0
None
Universal Trial Number (UTN)
Trial acronym
PROSPER-82
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Prostate Cancer 319674 0
Condition category
Condition code
Cancer 317602 317602 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Retro-prostatic hydrogel insertion (SpaceOAR®) followed by dose-escalated radiotherapy (82 Gy in 41 fractions)

Hydrogel (SpaceOAR®) insertion:
SpaceOAR® hydrogel is a commercially available system that is on the Australian Register of Therapeutic Goods (ID 179172) which is used to increase the separation of the rectum and prostate during radiotherapy to the prostate. The rectum is the most dose-limiting organ at risk during prostate radiotherapy, and increasing the separation between the rectum and prostate decreases the radiation dose to the rectum. This allows for dose-escalation to the prostate which may have benefits for cancer control.
Prior to SpaceOAR® insertion, participants had a baseline Computed Tomography (CT) scan for the purpose of radiotherapy planning and the determination of a baseline rectal Normal Tissue Complication Probability (NTCP). Participants were instructed to have a comfortably full bladder and empty rectum for the CT scan. Following this scan, participants were scheduled to undergo insertion of the SpaceOAR hydrogel.
The SpaceOAR® is a hydrogel consisting of 90% water and 10% polyethelene glycol. The SpaceOAR® is injected as a liquid between the prostate and rectum under ultrasound guidance, solidifying within seconds into a hydrogel that pushes the anterior rectal away from the high dose region that envelopes the prostate. The hydrogel is biocompatible and maintains a consistent space over a 3-6 month period, during which an eight week course of radiotherapy would take place. After 6 months, the hydrogel liquefies, allowing it to be absorbed into the body and then cleared.
SpaceOAR® hydrogel insertion was performed by a consultant level Radiation Oncologist or Urologist as a day procedure under a brief general anesthetic via the trans-perineal route and with antibiotic prophylaxis. The SpaceOAR® insertion took place approximately one week prior to the post-insertion CT scan for radiotherapy planning. The retro-prostatic space was hydro-dissected under ultrasound guidance and 10ml to 15ml of SpaceOAR® hydrogel was injected into the perirectal space using a transperineal approach under real-time ultrasound guidance. While under anesthetic, three gold-seed fidicuals were also inserted into the prostate to assist with target localisation during treatment, which is the standard of care for this population of men. A record of the insertion was documented by the radiation oncologist or urologist performing the procedure in the participant's electronic medical record.

Dose-Escalated Radiotherapy:
Approximately one week following SpaceOAR® insertion, and as part of radiotherapy planning, patients underwent Magnetic Resonance Imaging and a radiotherapy planning CT scan to assess the success of the SpaceOAR® insertion and for a consultant radiation oncologist to delineate the prostate, target volumes and organs at risk (rectum, rectal wall, ano-rectal junction, urethra, bladder and femurs).
The prescribed radiation dose to the prostate was 82Gy in 41 fractions, delivered at 5 fractions per week. If clinical dose constraints to the rectum could not be achieved, the participant was prescribed 78Gy in 39 fractions (5 per week). Participants received intensity modulated radiation therapy using 10MV photons and treatment was delivered using a Novalis Tx(TM) or Trilogy(TM) (Varian Medical Systems, USA) linear accelerator.
Intervention code [1] 319359 0
Treatment: Devices
Comparator / control treatment
Participants who received a SpaceOAR® insertion and received 78Gy in 39 fractions participants (ie. those whose rectal dose constraints could not be met for the 82Gy plan)
Control group
Dose comparison

Outcomes
Primary outcome [1] 325695 0
Incidence of clinically notifiable Gastrointestinal (GI) and Genitourinary (GU) toxicity and adverse events (CTCAE V4.0 Grade III or higher)
Timepoint [1] 325695 0
6 weeks following completion of radiotherapy, then 3 monthly up until 18 months, then 6 monthly up until 36 months post radiotherapy
Primary outcome [2] 325696 0
Patient determined quality of life using EORTC QLQ-C30 (version 3)
Timepoint [2] 325696 0
6 weeks following completion of radiotherapy, then 3 monthly up until 18 months, then 6 monthly up until 36 months post radiotherapy
Primary outcome [3] 326071 0
Patient determined quality of life using QLQ-PR25 assessment
Timepoint [3] 326071 0
6 weeks following completion of radiotherapy, then 3 monthly up until 18 months, then 6 monthly up until 36 months post radiotherapy
Secondary outcome [1] 388782 0
Patient reported tolerability following SpaceOAR® insertion, using a questionnaire specifically designed for the study
Timepoint [1] 388782 0
Within one week following SpaceOAR® insertion
Secondary outcome [2] 388783 0
Adverse events captured from SpaceOAR® hydrogel insertion, as reported by the radiation oncologist or urologist performing the procedure
Timepoint [2] 388783 0
Any time point within 36 months of radiotherapy
Secondary outcome [3] 388784 0
Peak acute GI toxicity due to radiotherapy using RTOG/EORTC acute and late radiation morbidity scoring tools
Timepoint [3] 388784 0
6 weeks following completion of radiotherapy, then 3 monthly up until 18 months, then 6 monthly up until 36 months post radiotherapy
Secondary outcome [4] 388785 0
Peak acute GU toxicity due to radiotherapy using RTOG/EORTC acute and late radiation morbidity scoring tools.
Timepoint [4] 388785 0
6 weeks following completion of radiotherapy, then 3 monthly up until 18 months, then 6 monthly up until 36 months post radiotherapy
Secondary outcome [5] 388786 0
Local disease control. Local disease control is defined as the absence of clinically significant disease on multi-parametric MRI.
Timepoint [5] 388786 0
36 months following radiotherapy
Secondary outcome [6] 390019 0
Biochemical disease free survival. Biochemical failure will be defined as an increase in serum PSA levels >2ng/mL from the post-radiotherapy nadir (Phoenix Criteria).
Timepoint [6] 390019 0
36 months following radiotherapy

Eligibility
Key inclusion criteria
1. Pathologically confirmed clinical stage T1 or T2 or T3 invasive adenocarcinoma of the prostate (any PSA, any Gleason score).
2. Males greater than 18 years old
3. Candidate for radical Intensity Modulated Radiotherapy.
4. ECOG performance status of 0 or 1.
5. Able to provide written informed consent, or consent can be provided by
authorized representative and approved by the appropriate Institutional
Review Board (IRB) of the respective clinical site.
6. Neo-adjuvant or adjuvant hormone therapy allowed
Minimum age
18 Years
Maximum age
No limit
Gender
Males
Can healthy volunteers participate?
No
Key exclusion criteria
1. Evidence of metastatic disease to the lymph nodes, bone or lung
2. Planned or previous pelvic or lymph node radiotherapy
3. Any other active malignancy (untreated, progressive or recurrent), except for
non-melanoma skin cancer.
4. Any inactive malignancy diagnosed within 5 years of entry, except for non- melanoma skin cancer.
5. Inflammatory bowel disease (active) such as Crohn’s disease and ulcerative colitis.
6. Active bleeding disorder.
7. Inflammatory bowel disease, chronic prostatitis or any urogenital anatomic
abnormality that would interfere with the ability to access the SpaceOAR® hydrogel injection site

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
All tests of treatment effects will be conducted at a two-sided alpha level of 0.05, unless otherwise stated. Any tests of interaction effects will be conducted at a two-sided alpha level of 0.10, unless otherwise stated.

The planned sample size has been chosen on the basis of the primary objective: to detect the incidence of clinically notifiable Gastrointestinal (GI) and Genitourinary (GU) toxicity and adverse events (CTCAE V4.0 Grade III or higher) up to 36 months following radiotherapy treatment.

The recommended minimal clinically important difference (MCID) for the CTCAE V4.0 is approximately equal to half a standard deviation(27) so the required sample size is given by:

N = 2(z1-a + zß)^2 x (s/d)^2

Where s is the standard deviation, d is the smallest detectable difference, and z1-a & zß are the standardised normal deviates relating to the specified type I & II error levels.
So, N = 2 x 7.84 x 4 = 63 patients, for 80% power & a two-sided a of 5%.
It is very likely that patients are likely to stick to their treatment regimen and follow up schedule, as two extra treatments and 3-6 monthly reviews are genuinely not considered a large burden on participants. If we allow for a realistic 5-10% loss to follow-up, the requirement is 70 patients be enrolled on this trial. If the dropout rate is higher, we intend to extend the trial duration to compensate.

The primary analysis of detecting clinically notifiable Gastrointestinal (GI) and Genitourinary (GU) toxicity and adverse events (CTCAE V4.0 Grade III or higher) up to 36 months following radiotherapy treatment will be a restricted maximum likelihood (REML)-based, mixed-effects model repeated measures approach (MMRM). The model will include the fixed, categorical effects of treatment, visit, and treatment-by-visit interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. An unstructured (co)variance structure will be used to model the within-patient errors. If the unstructured (co)variance matrix fails to converge, autoregressive, compound symmetry and toeplitz will be fitted. The Kenward- Roger approximation will be used to estimate denominator degrees of freedom. Significance tests will be based on least-squares means and Type III sum-of-squares, using a two-sided alpha of 5% (two-sided 95% confidence intervals) for all variables.

The same will also be performed using the EORTC QLQ-C30 and QLQ-PR25 instruments to determine patient quality of life as a primary endpoint.

Analyses will be implemented using SAS® PROC MIXED. The primary comparison is the contrast between treatment groups. Secondary evidence of efficacy from the primary analysis will be based on the main effect of treatment and the treatment- by-visit interaction terms from the MMRM analysis.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 18001 0
Epworth Freemasons (Clarendon Street) - East Melbourne
Recruitment hospital [2] 18002 0
Epworth Richmond - Richmond
Recruitment postcode(s) [1] 31967 0
3002 - East Melbourne
Recruitment postcode(s) [2] 31968 0
3121 - Richmond

Funding & Sponsors
Funding source category [1] 307164 0
Charities/Societies/Foundations
Name [1] 307164 0
Epworth Medical Foundation
Address [1] 307164 0
89 Bridge Road
Richmond
Victoria 3121
Country [1] 307164 0
Australia
Primary sponsor type
Hospital
Name
Epworth HealthCare
Address
89 Bridge Road
Richmond
Victoria 3121
Country
Australia
Secondary sponsor category [1] 307756 0
None
Name [1] 307756 0
Address [1] 307756 0
Country [1] 307756 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307278 0
Epworth HealthCare HREC
Ethics committee address [1] 307278 0
89 Bridge Road
Richmond
Victoria 3121
Ethics committee country [1] 307278 0
Australia
Date submitted for ethics approval [1] 307278 0
Approval date [1] 307278 0
24/10/2013
Ethics approval number [1] 307278 0
611-13

Summary
Brief summary
Prostate cancer is the most common cancer in men, accounting for 25% of all cancer, with approximately 75% of those cancers arise posteriorly in the peripheral zone of the gland just adjacent to the rectum. Dose escalation in prostate cancer radiotherapy leads to improved tumor control rates however a dilemma arises in the balance between radiation dose and unacceptable rectal adverse effects (including diarrhoea and bleeding) which can complicate therapy in up to 20% of patients (due to the proximity of the prostate and the rectum). In some cases symptoms may evolve into a chronic course, negatively impacting on patients long term quality of life. Researchers have tried various technologies to protect rectal tissue when radiation is being delivered to the prostate. One such paradigm is the use of an inert protective synthetic hydrogel (made up of 90% water) called SpaceOAR, that is currently the only commercially available product for prostate-rectum separation. SpaceOAR is a transperineal inserted spacer (TIS) that is injected as a liquid into the anterior perirectal fat. When it solidifies, it forms a small protective barrier and space between the rectum and the prostate for the duration of radiotherapy treatment. Over a few months SpaceOAR dissolves and is absorbed by the body. A reasonable body of accumulated published literature has reported on the clinical utility of rectal spacers in phase II cohorts involving men undergoing external beam and brachytherapy to standard doses, with significant decrease in rectal toxicity. These results are echoed by the experience of Epworth Radiation Oncology, using conventional doses. The current trial is a prospective, non-randomized, single arm open-label study aimed at assessing the safety and efficacy of treating men with clinically localized prostate cancer to 82Gy using Intensity modulated Radiotherapy following the insertion of rectal SpaceOAR® hydrogel. The primary aims of this trial are to assess the inicidence of clinically notifiable toxicity and impact of health-related quality of life up to 36 months following radiotherapy.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106658 0
Dr Andrew See
Address 106658 0
Level 4, The Epworth Centre
32 Erin Street Richmond, VIC, 3121
Country 106658 0
Australia
Phone 106658 0
+61 3 9936 8269
Fax 106658 0
Email 106658 0
andrew.see@icon.team
Contact person for public queries
Name 106659 0
Ms Skye Nolan
Address 106659 0
Level 5, The Epworth Centre
32 Erin Street Richmond, VIC, 3121
Country 106659 0
Australia
Phone 106659 0
+61 3 9936 8277
Fax 106659 0
Email 106659 0
skye.nolan@icon.team
Contact person for scientific queries
Name 106660 0
Dr Andrew See
Address 106660 0
Level 4, The Epworth Centre
32 Erin Street Richmond, VIC, 3121
Country 106660 0
Australia
Phone 106660 0
+61 3 9936 8269
Fax 106660 0
Email 106660 0
andrew.see@icon.team

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary